Publications cited throughout this disclosure are incorporated in their entirety herein by reference.
Histamine is a well established modulator of neuronal activity. At least four subtypes of histamine receptors have been reported in the literature—H1, H2, H3, H4. The histamine H3 receptors play a key role in neurotransmission in the central nervous system. The H3 receptor was discovered in 1983 originally on histamine-containing neurons where it was shown to function presynaptically, regulating the release and synthesis of the biogenic amine histamine, now a well established neurotransmitter. (Arrang, J. M.; Garbarg, M.; Schwartz, J. C., Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983, 302, (5911), 832-7) H3 receptors are predominately expressed in the brain, localizing to the cerebral cortex, amygdala, hippocampus, striatum, thalamus and hypothalamus. H3 receptors are also localized presynaptically on histaminergic nerve terminals and act as inhibitory autoreceptors (Alguacil L. F.; Perez-Garcia C. Histamine H3 Receptor: A potential drug target for the treatment of central nervous systems disorders. Current Drug Targets-CNS & Neurological Disorders 2003, 2, 303-131; Passani, M. B.; Lin, J. S.; Hancock, A.; Crochet, S.; Blandina, P., The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol Sci 2004, 25, 618-25; Leurs, R.; Bakker, R. A.; Timmerman, H.; de Esch, I. J., The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 2005, 4, (2), 107-20; Celanire, S.; Wijtmans, M.; Talaga, P.; Leurs, R.; de Esch, I. J., Keynote review: histamine H3 receptor antagonists reach out for the clinic. Drug Discov Today 2005, 10, (23-24), 1613-27; Witkin, J. M.; Nelson, D. L., Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol Ther 2004, 103, 1-20). When these receptors are activated by histamine, histamine release is inhibited. H3 receptors can also be found in the periphery (skin, lung, cardiovascular system, intestine, GI tract, etc). H3 receptors are also involved in presynaptic regulation of the release of acetylcholine, dopamine, GABA, glutamate and serotonin (see Repka-Ramirez M. S. New concepts of histamine receptors and actions. Current Allergy and Asthma Reports 2003, 3, 227-231; Chazot P. L.; Hann V. H3 histamine receptor isoforms: New therapeutic targets in the CNS? Current Opinions in Investigational Drugs 2001, 2, 1428-1431; Leurs R.; Blandina P.; Tedford C.; Timmerman H. Therapeutic potential of histamine H3 receptor agonists and antagonists. Trends in Pharmacology 1998, 19, 177-183). The H3 receptor demonstrates a high degree of constitutive or spontaneous activity (e.g., receptor is active in the absence of agonist stimulation) in vitro and in vivo, thus, ligands to the receptor can display, agonist, neutral antagonist or inverse agonist effects.
The location and function of histaminergic neurons in the CNS suggests that compounds interacting with the H3 receptor may have utility in a number of therapeutic applications including narcolepsy or sleep/wake disorders, feeding behavior, eating disorders, obesity, cognition, arousal, memory, mood disorders, mood attention alteration, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain, stress, migraine, motion sickness, depression, psychiatric disorders and epilepsy (Leurs et al, 2005; Witkin and Nelson, 2004; Hancock, A. A.; Fox, G. B. Perspectives on cognitive domains, H3 receptor ligands and neurological disease. Expert Opin. Investig. Drugs, 2004, 13, 1237-1248; Esbenshade, T. A.; ox, G. B.; Cowart, M. D. Histamine H3 receptor antagonists: Preclinical promise for treating obesity and cognitive disorders. Molecular interventions 2006, 6, 77-88). An H3 antagonist/inverse agonist could be important for gastrointestinal disorders, respiratory disorders such as asthma, inflammation, and myocardial infarction.
Thus, there is a need for novel classes of compounds that possess the beneficial properties. It has been discovered that compounds of the present invention, referred to herein as substituted phenoxypropylcycloamine derivatives, are useful as agents for treating or preventing various diseases or disorders disclosed herein.